While many factors are involved in precipitating relapse in recovering drug addicts, life stressors are often reported as a reason for the return to drug use. Methamphetamine abuse is on the rise yet little in known about the potential role of stress in relapse with this drug of abuse. We are taking a multifaceted approach to examining this issue. In these experiments, rats have access to two levers in their cage. When one lever is pressed, a signal is sent to a pump that delivers a small amount of methamphetamine through an indwelling jugular catheter. Pressing the second lever does not result in an injection so, rats quickly develop a clear preference for the lever that provides methamphetamine. Rats are allowed to self-administer methamphetamine for two weeks before we disconnect the syringe containing the drug. Once the syringe is removed, neither lever will provide access to methamphetamine. Over the course of a week the rats learn that they can no longer get methamphetamine and the number of lever presses is greatly reduced (extinction). At this point we subject the rat to a laboratory stressor or pharmacologic agent and measure the number of times the rat presses the levers. If the rat selectively increases its responses on the lever that was previously associated with methamphetamine, we interpret this behavior as methamphetamine seeking (relapse). We demonstrated for the first time that two very different laboratory stressors (mild foot shock or puffs of air) result in methamphetamine seeking in our rat model of drug relapse. We also found that each stressor differed in the degree of methamphetamine seeking after the stressor was terminated. In the case of air puffs delivered through the floor of the cage, rats only engaged in drug seeking during the hour that air puffs were present, but not following the termination of the stimulus. Mild foot shocks were delivered in half second bursts over the course of five minutes. In this case, rats engaged in methamphetamine seeking for an hour after the stimulus was removed. To gain insight into the possible mechanisms involved in stress induced methamphetamine seeking, we examined whether a compound that is known to produce stress-like effects in humans such as yohimbine, could induce methamphetamine seeking. In contrast to air puffs or foot shock, yohimbine produced a striking increase in methamphetamine seeking that was present throughout the entire post treatment observation time with no sign of returning to baseline three hours after the yohimbine treatment. We are currently examining the neural mechanisms of yohimbine induced methamphetamine seeking using a combination of in situ hybridization and immunocytochemistry. Detailed information about how a drug such as yohimbine can lead to drug seeking may provide the basis for prevention of stress induced relapse by using medications that blunt the effects of stress on neural circuits involved in drug relapse. We also discovered that yohimbine induces drug seeking in rats that had been abstinent from methamphetamine use for as long as 51 days. Considering that the average life span of a laboratory rat is about two years, a drug-free period of 51 days is a significant amount of time for this species. Our finding that rats are vulnerable to relapse following prolonged withdrawal lead to our examination of long-term neuroadaptions to methamphetamine self-administration.